Mild traumatic brain injury (TBI) can cause emotional and cognitive deficits that last for months to years after the traumatic event. These deficits prominently include depression and an inability to extinguish fearful memories (leading to fear perseveration), which are part of the Post Concussion Syndrome (PCS) as defined in the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV). Mild TBI typically results from a closed-head insult after a primary blast shock wave, a blow to the head, or head acceleration - deceleration during a collision. It is an extremely frequent occurrence during military combat, sports, recreational activities, and vehicular accidents and thus constitutes a significant public mental health problem. The major brain pathology observed after mild TBI is diffuse axonal injury, although persistent neuronal dysfunction is suspected as well. The precise brain regions whose connectivity and function are disrupted by mild TBI so as to cause neuropsychiatric deficits have been uncertain. Based on our initial findings, we propose to use a mouse model of mild TBI to study the role of electrophysiological abnormalities in medial prefrontal cortex (mPFC) in the genesis of fear perseveration and depression, two of the more disabling neuropsychiatric sequela of mild TBI, for which there is currently no treatment. We will also confirm that a novel drug that we have shown to reduce depression and fear after mild TBI in mice, does so by normalizing mPFC coherence. Our proposed studies are based on our preliminary findings using multi-site recordings of neuronal activity in mice with mild TBI, caused by a precisely controlled overpressure air blast restricted to the cranium overlying the left forebrain. Our results suggest that abnormal phase coherence of neuronal firing in the medial prefrontal cortex (mPFC) is persistently present in mice that show enduring depression and an inability to extinguish fear memories up to one year after they experienced mild TBI. By contrast, mice that had experienced a subconcussive air blast or a sham air blast showed normal coherence of neuronal firing in mPFC and no depression or perseverative fear afterwards. Furthermore, treating mice with the novel drug (the cannabinoid type-2 receptor inverse agonist SMM-189) not only ameliorated fear and depression at 1 month after mTBI, it also restored coherence in the mPFC to normal values. Confirmation of our preliminary findings is thus likely to advance our understanding of the neuronal mechanisms behind persistent depression and fear after mild TBI, and may provide an electrophysiological signature that can be used to identify those humans whose persistent depression and fear is likely to arise from mTBI. We therefore propose to test the hypothesis that coherence of neuronal oscillations in mPFC is tightly associated with and thus causal to the persistent depression and fear after mild TBI. We also propose to test the hypothesis that SMM-189 rescues mTBI related fear and depression deficits in mice by restoring normal neuronal coherence in the mPFC, and that further investigation of SMM-189 may thus lead to a possible pharmacological treatment for mTBI.